NO811065L - PROCEDURE FOR THE PREPARATION OF CERTAIN PYRIMIDON DERIVATIVES - Google Patents

Description

This invention relates to the production of therapeutic

active pyrimidone derivatives which are particularly useful as histamine r^ antagonists.

Histamine, a physiologically active compound that is

endogenous in mammals, exerts its action by reacting with certain points called receptors. One type of receptor is known as a histamine H 2 receptor (Ash and Schild, Brit.

J. Pharmac. 1966, 27, 427) and the effects of histamine mediated through these receptors are blocked by agents commonly called "antihistamines" (histamine H 2 antagonists), a common example of which is mepyramine. Another type of histamine receptor is known as the R^ receptor (Black et al.

Nature 1972, 236, 385). These receptors are not blocked by mepyramine, but are blocked by burimamide. Compounds that block these histamine P^ receptors are called histamine H^ antagonists.

Histamine f^ antagonists are useful for the treatment of disease states caused by the biological effects of histamine mediated through Hj receptors, e.g. as inhibitors of gastric acid secretion, in the treatment of inflammation mediated through histamine I-^ receptors, and as agents acting on the cardiovascular system, e.g. as inhibitors of effects of histamine on blood pressure mediated through histamine P^ receptors.

Cimetidine is an example of a histamine I-^ antagonist. Cimetidine has been shown to be useful in the treatment of duodenal, gastric, recurrent and stomal ulceration and reflux oesophagitis and for the treatment of patients at high risk of upper gastrointestinal bleeding.

In some physiological conditions, the biological effects of histamine are mediated through both histamine H-^ and r^-receptors, and blocking both types of receptors is useful for the treatment of such conditions. These conditions include inflammation mediated by histamine, e.g. inflammation of the skin,

and. the hypersensitivity reactions due to the action of histamine at H^ and ^" receptors, eg allergies.

A class of pyrimidone derivatives has now been discovered

which are particularly active as histamine F^ antagonists.

According to the invention, a method for the production of compounds of formula (I) is provided:

where W is a 2-furanyl or 2-thienyl group which is optionally substituted in the 5-position with a group R 1 R 2 NfCl ) ;

a phenyl group substituted in the 3- or 4-position by a

12

group R-R (Ct^) -; a 4-imidazolyl group which is optionally substituted in the 5-position with methyl or bromine; a 2-pyridyl group which is optionally substituted in the 3-position by C^_^alkyl, C^_4 alkoxy, halogen, amino or hydroxy; a 2-thiazolyl group or a 2-guanidino-4-thiazolyl group;

X is .methylene or sulfur, and Y is methylene or, provided

that X is methylene and W is a substituted phenyl group, oxygen;

Z is hydrogen or C^_^alkyl; and B is a 2-furanyl or 2-thienyl group which is substituted in the 5-position by a group

12

R R N(CH_) -; a phenyl group substituted in 3- or 4-side addition

12

with a group R R NfCl-^) - or a 3-pyridyl group. substituted in the 5- or 6-position or a 4-pyridyl group substituted in the 2-position or a 2-pyridyl group substituted in the 4- or 5-1 2

position with a group R R N(CH ) ;

12 .£rn

R and R are C^_^ alkyl or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or morpholino group;

merl ten 14;

and pharmaceutically acceptable acid addition salts thereof.

Z can e.g. be hydrogen, methyl, ethyl, n-propyl or

n-butyl, but preferably Z is hydrogen.

With respect to B, examples of C._ . alkyl groups such as 12 l 4 • -

R and R can represent methyl, ethyl and n-propyl.

1 2

Preferably, both R" and R are methyl, especially when m is 1.

Examples of special groups denoted by B are thus 3- and 4-dimethylaminomethylphenyl, 5-dimethylaminomethyl-2-thienyl, 5-dimethylaminomethyl-2-furanyl, 5-dimethylaminomethyl-3-pyridyl, 6-dimethylaminomethyl-3-pyridyl and 2- dimethylaminomethyl-4-pyridyl. Preferably, B is 5-dimethylaminomethyl-2-furanyl, 6-dimethylaminomethyl-3-pyridyl or 2-dimethylaminomethyl-4-pyridyl.

A group of compounds of formula I is that where W is phenyl substituted in the 3- or 4-position by R 1 R 2NfCf^)^.

In this group, Y is preferably oxygen and X is methylene,

12

and the group R R NiCR^)^- is preferably in the 3-position.

A further group of compounds of formula I is that where W is 2-furanyl or 2-thienyl optionally substituted in

12

5- position with R R N(CH2) -; 4-imidazolyl optionally substituted in the 5-position with methyl or bromine; 2-pyridyl optionally substituted in the 3-position by C^_^alkyl, ^ alkoxy, halogen, amino or hydroxy; 2-thiazolyl or 2-guanidino-4-thiazolyl. In this group of compounds, Y is preferably methylene and X sulphur.

Examples of and preferred meanings for m and C._. alkyl-12

groups for R and R in W in both of the above groups of compounds are as indicated above for B.

A particular subclass of compounds of formula I within the latter group is that where W is a 2-furanyl or 2-thienyl group which is optionally substituted in the 5-position with

12

the group R R NKCI-^) -; a 4-imidazolyl group optionally substituted in the 5-position with methyl or bromine; a 2-thiazolyl group or a 2-guanidino-4-thiazolyl group.

Within this subclass, W can in particular be 2-furanyl 12

and 2-thienyl substituted in the 5-position with the group R R N(CH„) -,

12

especially where R and R are both methyl and m is 1, and these compounds are considerably more active as H 2 antagonists than those where W is 2-furanyl or 2-thienyl.

Of these special meanings, W is preferably 5-dimethyl-aminomethyl-2-furanyl.

A further subclass of compounds of formula (I) are those where B and W are the same and mean 2-furanyl or 2-thienyl 12 1 substituted in the 5-position by a group R R N(CH„) - where R and 2 ^ m R is as stated above, and m is 1.

Examples of compounds of formula I are: 2-[2-(5-methyl-4-imidazolylmethylthio)-ethylamino]-5-(3-dimethylaminomethylbenzyl)-4-pyrimidone,

2-[ 2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone,

2-[2-(5-dimethylaminomethyl-2-thienylmethylthio)ethylamino]-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone,

2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone,

2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-5-(4-dimethylaminomethylbenzyl)-4-pyrimidone,

2-[3-(3-dimethylaminomethylphenoxy)propylamino]-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone,

2-[3-(3-dimethylaminomethylphenoxy)propylamino]-5-(4-dimethylaminomethylbenzyl)-4-pyrimidone and their pharmaceutically acceptable salts.

Examples of compounds of formula I with the preferred group B are: 2-[2-(5-methyl-4-imidaz.olylmethylthio)ethylamino]-5-(5-dimethyl-aminomethyl-2-furanylmethyl)-4- pyrimidone,

2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-5-(5-dimethylaminomethyl-2-furanylmethyl)-4-pyrimidone,

2-f 3-(3-dimethylaminomethylphenoxy)propylamino]-5-(5-dimethylaminomethyl-2-furanylmethyl)-4-pyrimidone,

2-[2-(5-m'ethyl-4-imidazolyImetyItio)ethylamino]-5-(6-dimethyl-aminomethyl-3-pyridylmethyl)-4-pyrimidone and their pharmaceutically acceptable salts.

Examples of compounds of formula I with the preferred group W are: 2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5- (5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone,

2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(3-dimethylaminomethylbenzyl)-4-pyrimidone, and their pharmaceutically acceptable salts.

Examples of compounds with the preferred groups W, Y, X and B are: 2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(5-dimethylaminomethyl-2-furanylmethyl)-4-pyrimidone,

2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(2-dimethylaminomethyl-4-pyridylmethyl)-4-pyrimidone,

2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(6-dimethylaminomethyl-3-pyridylmethyl)-4-pyrimidone and their pharmaceutically acceptable salts.

Compounds of formula (I) are bases and can form pharmaceutically acceptable salts with acids, e.g. with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid and maleic acid.

According to the invention, the compounds of formula (I) and their salts can be prepared by a compound of formula (II):

where W and Y are as defined under formula (I) and D is -XCH2CH2NH2or, provided that Y is methylene, a thiol-replaceable group, reacted with a pyrimidone derivative of formula (III):

where B"*" is 2-furanyl, 2-thienyl or B, where B and Z are as indicated under formula (I), and A is a group which can be replaced by an amine when D is -XCH2CH2NH2, or A is HS -CH2-CH2NH when D is a thiol-displaceable group, and then, when B"*"

is 2-furanyl or'2-thienyl, and optionally when W is 2-furanyl or 2-thienyl, the thus produced product is reacted with a

12 Mannich reagent which provides the substituent R R N(CH2)m~where m is 1, and then the thus prepared compound of formula (I) is converted into a salt..

Examples of groups that can be replaced by thiol are

hydroxy, alkanoyloxy (preferably acetoxy), methanesulfonyloxy,

p-Toluenesulfonyloxy, trifluoromethanesulfonyloxy, _ - alkoxy (preferably methoxy), chlorine, bromine and triarylphosphonium (preferably triphenylphosphonium).

When W contains the group R 1 R 2N(CH 2 )m~, D is preferably hydroxy, C^_^ alkoxy or acetoxy, and the reaction is carried out under acidic conditions, e.g. in acetic acid or in aqueous hydrochloric or hydrobromic acid. When W is 2-furanyl or 2-thienyl, D is preferably sulfonyloxy, chlorine, bromine or triarylphosphonium, and the reaction is carried out in the presence of a base, e.g.

in the presence of sodium ethoxide in ethanol. Preferably, D is hydroxy or chlorine.

Examples of leaving groups A which can be replaced by amines are nitroamino, C^_^alkylthio, chlorine or bromine. Preferably, the group A is nitroamino.

The process where A is a leaving group that can be replaced by amines can be carried out at elevated temperature,

e.g. 150°C, or under reflux in the presence of a high-boiling solvent, e.g. in pyridine. When A is nitroamino, the reaction can be carried out in an alkanol, e.g. ethanol under reflux.

Mannich reagents can be prepared in situ from an amine

12 12

R R NH where R and R are as indicated under formula (I), and

1 2

formaldehyde, or when R and R are both c^_^ alkyl, it can e.g. a di-(C 1-2 alkyl)-methylene ammonium salt is used,

especially dimethylimethyleneammonium chloride or iodide, or a bis-(di-C-^_^ alkylamino)methane, especially bis(dimethylamino)methane.

This method which includes a Mannich reagent is

an example of the Mannich reaction and can be carried out under conditions normally used for this type of reaction.

Acid addition salts of compounds of formula (I) can conveniently be formed from the corresponding bases by standard methods, e.g. by reacting the base with an acid in a C^_^alkanol or by using ion exchange resins to form the desired salt. Salts of compounds of formula (I) can. are also inter-converted using an ion exchange resin.

Compounds of formula (II) are known or can be prepared by known methods. In particular, compounds of formula (II) where D is -XCH 2 CH 2 NH 2 [amines of formula (II)] are well known, e.g. those where W is a 2-thiazolyl group, a 4-imidazolyl group optionally substituted in the 5-position by methyl or bromine, or a 2-pyridyl group optionally substituted in the 3-position by C-^_^alkyl, C^_^alkyl , halogen, amino or hydroxy, and Y is CH 2 and X is CH 2 or sulphur, are described in British patents 1305547, 1305548 and 1338169 and in Belgian patents 844504 and 846452. Amines of formula (II) where W is 2-furanyl and 2-thienyl substituted in the 5-position with a group R 1 R 2N^CH^)m_ and Y is CH 2 and X is CH 2 or sulphur, are described in Belgian patents 857388 and 867105. Amines of formula (II) where W is a phenyl group substituted in 3- or 4-position with a group R 1 R 2N(CH 2 ) - and Y is oxygen or methylene and X is methylene or sulphur, is described in Belgian patent 867106 and European patent application 80300478.7.

Amines of formula (II) where W is 2-guanidino-4-thiazolyl,

Y is methylene and X is methylene or sulphur, is described in British patent 2001624A.

Pyrimidone derivatives of formula (III) where B''" is 2-furanyl or 2-thienyl can be prepared by known methods such as, for example, described in European patent 0 004 793 and Belgian patents 846452 and 849810.

Pyrimidones of formula (III) where B"^ is B and A is nitroamino, can be prepared by reacting nitroguanidine with a 3-oxoester of formula (IV):

where B and Z are as defined under formula (III), and R is C₁₋₋alkyl, - in the presence of base.

Examples of suitable bases include alkali metal hydroxides and C^_^ alkoxides, sodium hydride and quaternary ammonium hydroxides, e.g. benzyltrimethylammonium hydroxide. Preferably the base is sodium ethoxide or sodium methoxide. The reaction can be carried out in the presence of a solvent, and the choice of this is not critical for a successful result, provided that it is approximately inert to reagents and product. Preferably, the solvent is a C 1-4 alkanol (eg methanol, ethanol or propanol) or dimethylformamide.

Pyrimidone derivatives of formula (III) where B is B and

A is C^_^alkylthio, can be prepared by reacting a (3-oxoester of formula (IV) above with thiourea to form a 2-thiouracil of formula (V):

where Z and B are as defined under formula (III), which can then be alkylated with a C1-4 alkyl halide or sulfate.

Pyrimidones of formula (III) where B^~ is B and A is chlorine or bromine, can be prepared by reacting a 3-oxoester of formula (IV) with guanidine to form an aminopyrimidone (VI):

where Z and B are as defined under formula (III), and the amino group is converted to chlorine or bromine by reacting the aminopyrimidone compound (VI) with sodium nitrite, the corresponding hydrohalic acid and the corresponding copper (I) halide.

Pyrimidones with formula; (III) where A is HS-CP^Cr^NH- can be prepared by an amine of formula (VII): GS-CH2CH2NH2(VII)'

where G is hydrogen or a thiol-protecting group (e.g. trityl, 4-methoxybenzyl or the rest of the disulfide, namely NH2CH2CH2S-), is reacted with a pyrimidone of formula (III) where A is a group that can be replaced by amine as previously mentioned, and then the thiol-protecting group is removed.

Pyrimidone derivatives of formula (III) where B is B, i.e. compounds of formula (Illa):

where A is a group that can be replaced by an amine or is HSCI-^Cr^NH-, and Z and B are as defined under formula (I), are new.

Amines of formula (VII) are known or can be prepared

in analogy with known methods.

Compounds of formula (II) where D is -OH are known or

can be produced by analogy with known methods.

The activity of the compounds of formula (I) as histamine I-^-. antagonists can be demonstrated by the inhibition of histamine-stimulated secretion of gastric acid from lumen-perfused stomachs of urethane-anesthetized rats. This method is described in Ash and Schild, Brit. J. Pharmac. Chemother., _27, 247 (1966). The connections

in the following examples 1 to 14 caused 50% inhibition of maximal acid secretion at doses below 0.5 micromol per kg i.v. Their activity as histamine I-^ antagonists can also be demonstrated by their ability to inhibit other effects of histamine which, according to the above-mentioned article by Ash and Schild, are not mediated by means of I-^ receptors. E.g. inhibit the effects of histamine on an isolated guinea pig heart atrium. The strength of these compounds is illustrated by the effective dose that induces. 50% inhibition of histamine-induced tachycardia in it

— 6

isolated guinea pig cardiac atria (less than 10 molar).

In order to use a compound of formula (I) or a pharmaceutically acceptable salt thereof for medicinal purposes, the compound is normally prepared according to standard pharmaceutical practice as a pharmaceutical preparation.

Pharmaceutical preparations contain a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable carrier.

Compounds of formula (T) and their pharmaceutically acceptable

acid addition salts can be administered orally, parenterally,

cutaneously or rectally.

Compounds of formula (I) and their pharmaceutically acceptable salts which are active when administered orally can be prepared as syrups, tablets, capsules and lozenges.

A syrup preparation will normally consist of a suspension or solution of the compound or a salt thereof in a liquid carrier, e.g. ethanol, glycerol or water with a flavoring or coloring agent. When the preparation is in the form of a tablet, any pharmaceutical carrier that is normally used for the production of solid preparations can be used. Examples of such carriers include magnesium stearate, starch, lactose and sucrose.

Typical parenteral preparations consist of a solution or suspension of the compound or a salt thereof in a sterile, aqueous vehicle or a parenterally acceptable oil.

Typical preparations for application to the skin include liquids

and creams where the compound of formula (I) or a salt thereof is dispersed in a liquid carrier.

A typical suppository preparation comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binder and/or lubricant such as e.g. gelatin or, cocoa butter or other low-melting vegetable waxes or fats.

The preparation is preferably in unit dose form, e.g. one

tablet or capsule, so that the patient can self-administer it in a single dose.

Each dosage unit preferably contains from 15 to 250 mg

of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, calculated as the free base.

The pharmaceutical preparations are normally administered to humans to treat gastric and duodenal ulcers and other conditions caused or aggravated by stomach acid, on

the same general way as that used for known histamine H^-antagonists, taking into account the strength of the new compound in relation to known histamine I-^-antagonists when choosing dosage amounts. The daily dose for an adult patient is an oral dose between 15 and 1500 mg and preferably between 20 and 250 mg, or an intravenous, subcutaneous or intra-

intramuscular dose of between 1.5 and 150 mg and preferably between 5 and 20 mg of a compound of formula (I) or a

pharmaceutically acceptable salt thereof calculated as the free base, the preparation being administered 1 to 6 times daily.

The following examples illustrate the invention.

Example 1

(i) 5-(Dimethylaminomethyl)thiophene-2-carboxaldehyde (40.09 g) and piperidine (3 ml) were added to a solution of malonic acid (24.65 g) in pyridine (150 ml). The mixture was stirred under reflux for 7 hours. During the reaction a solid was formed

substance precipitated and slowly dissolved again. The solution was allowed to cool and was then poured into 2M hydrochloric acid (150 ml). The volume of the solution was reduced to approx. 120 ml by evaporation under reduced pressure, and it was extracted with diethyl ether. The ether extracts were washed with water. The aqueous phase was cooled and the solid which precipitated was filtered off and washed with water-isopropanol. More solids were obtained by evaporating the filtrate to approx. 100 ml and adding isopropanol and cooling the mixture in ice for approx. 15 minutes. This solid was filtered off and washed with isopropanol. The solids were collected and recrystallized from isopropanol-water to give 3-(5-dimethylaminomethyl-2-thienyl)acrylic acid (27.45 g),

sm.p. 223.5-225°C.

(ii) 3-(5-dimethylaminomethyl-2-thienyl)acrylic acid (33.31 g)

was dissolved in ethanol (150 mL) and acidified with concentrated sulfuric acid (10 mL). The solution was refluxed for 18 hours, allowed to cool and then poured into a mixture of

ice and aqueous ammonia (0.88% w/w 30 ml). The ice was allowed to melt, and then the aqueous solution was extracted with ether, and the combined ether extracts were washed with water and dried over MgSO 4 . Ether was evaporated under reduced pressure to give ethyl 3-(5-dimethylaminomethyl-2-thienyl)-acrylate (30.30 g)

as a straw colored oil.

(iii) A solution of ethyl 3-(5-dimethylaminomethyl-2-thienyl)acrylate (30.30 g) in ethanol (175 ml) was hydrogenated (initial pressure 344 kPa) for a total of 8.5 hours at a temperature between 55 and 60°C in the presence of a 10% palladium-on-charcoal catalyst (about 10 g) which was used in two portions. It

first portion was added to the reaction mixture at once,

and the second after 5.5 hours. The catalyst was filtered off through diatomaceous earth and washed with ethanol. The filtrate was evaporated under reduced pressure to give ethyl 1-3-(5-dimethylamino-methyl-2-thienyl)-propionate (29.91 g) as a colorless oil.

(iv) A mixture of ethyl 3-(5-dimethylaminomethyl-2-thienyl)-propionate (29.91 g) and ethyl formate (13.77 g, 15 ml) was added dropwise with stirring to a suspension of sodium hydride in oil (57% in oil; 6.52 g) in 1,2-dimethoxyethane (45 mL) which had been precooled to -5°C. The temperature was maintained

-5 to -2°C during addition. The mixture was then allowed to gradually warm to room temperature and allowed to stand for approx. 16 hours. The mixture was poured onto ice which melted to give a brown solution which was evaporated to dryness to give an oil. The oil was mixed with hot acetone and the mixture was filtered through diatomaceous earth and the acetone was evaporated to give ethyl 3-(5-dimethyl-aminomethyl-2-thienyl)-2-formyl-propionate (32.92 g) as an oil. (v) Nitroguanidine (16.92 g containing 25% water) and methanol (35 mL) were added to a solution of sodium (4.21 g) in methanol (95 mL) and the mixture was heated under reflux with stirring for 45 minutes. A solution of ethyl 3-(5-dimethylaminomethyl-2-thienyl)-2-formyl-propionate (32.85 g) in methanol (90 mL) was then added to the mixture under reflux with stirring for 1.25 h . The mixture thus obtained was heated under reflux with stirring for a further 22 hours. The methanol was evaporated under reduced pressure and the residue dissolved in water. The solution thus obtained was extracted with chloroform, and the combined extracts were washed with water. The aqueous phase and water washings were collected, and the water was evaporated under reduced pressure. The residue was dried by azeotroping with isopropanol. The residue was mixed with a small amount of water, heated and allowed to cool, and the insoluble residue was filtered, washed with water and ethanol and dried to give 2-nitro-amino-5-(5-dimethylamino-2-thienylmethyl) ) -4-pyrimidone (6.53 g), m.p. 228-232°C (dec.).

. (vi) A mixture of 2-(5-methyl-4-imidazolylmethylthio)-

ethylamine (1.37 g) and 2-nitroamino-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone (2.32 g) in ethanol were heated under reflux for 48 hours. The ethanol was evaporated under reduced pressure to give 2-[2-(5-methyl-4-imidazolyl-methylthio)ethylamino]-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone as a glassy residue which was washed with hot water when decanting. The residue was dissolved in isopropanol and a solution of ethanolic hydrochloric acid (3 ml) was added. Excess solvent was removed under reduced pressure,

and the trihydrochloride crystallized as a pale tan solid (3.11 g). The solid was recrystallized from methanol-ethanol (2.36 g) 185.5-188.5°C.

Example 2

A mixture of 2-(5-dimethylaminomethyl-2-furanylmethylthio)-ethylamine (1.64 g) and 2-nitroamino-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone (2.01 g) in ethanol (10 ml) was heated under reflux for 30 hrs. The ethanol was evaporated in vacuo to give 2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5^(5-dimethylaminomethyl-2-thienyl-methyl)-4-pyrimidone as a brown oil which was washed with hot water when decanting. The residue was dissolved in isopropanol and an excess of ethanolic hydrochloric acid was added to the solution.

Excess solvent was evaporated in vacuo

and the residue was recrystallized from isopropanol-methanol containing ethanolic HCl and then from ethanol-methanol to give the trihydrochloride (2.72 g), m.p. 197-200°C.

Example 3

The [2-(2-guanidino-4-thiazolylmethylthio)]-ethylamino dihydrochloride (2.43 g) was dissolved in ethanolic sodium ethoxide solution (0.37 g sodium, 15 mL ethanol). The solution was stirred for 1 hour and the sodium chloride which had precipitated during this time was removed by filtration. 2-Nitroamino-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone (2.00 g) was added to the solution, and the mixture was heated under reflux for 48 hours. The ethanol was evaporated under reduced pressure and the residue was precipitated twice from solution in a min

possible amount of ethanol by adding water drop by drop. 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone was collected as an oily solid.

The oily solid was dissolved in ethanol and

decolorized with charcoal. The solvent was evaporated under reduced pressure from the decolorized solution to give a yellow oil which solidified on trituration to give a white solid which was recrystallized from diethyl ether/isopropanol and then from ethanolic hydrochloric acid/isopropanol to give the trihydrochloride (0.59 g ), sm.p. 164-6°C.

Example 4

(i) A mixture of 4-dimethylaminomethylbenzaldehyde (32.64 g), monoethyl malonate (29.07 g), pyridine (100 mL) and piperidine (2 mL) was heated under reflux with stirring for 5 hours. The pyridine was evaporated under reduced pressure and the oily residue was extracted with diethyl ether. The combined ether extracts were washed with water and dried over magnesium sulfate. The ether was evaporated under reduced pressure to give ethyl 4-(dimethylaminomethyl)-cinnamate as a light, straw colored oil (46, 57 g).

(ii) A solution of ethyl 4-(dimethylaminomethyl)-cinnamate in ethanol (170 ml) was hydrogenated using palladium-

on charcoal (0.5 g) at a temperature of 36-37°C and hydrogen at an initial pressure of 344 kPa until the calculated hydrogen

recording was registered.

The solution was filtered through diatomaceous earth to

removed the catalyst, and the filter medium was washed with ethanol.

The combined filtrate and washings were evaporated to give

.ethyl 3-(4-dimethylaminomethylphenyl)-propionate (45.97 g) as a

light, straw-colored oil.

(iii) A mixture of ethyl 3-(4-dimethylaminomethylphenyl)-

propionate (45.97 g) and ethyl formate (21.70 g) were added dropwise with stirring to a suspension of sodium hydride (50% in oil, 11.72 g) in dimethoxyethane (70 ml) which had been pre-cooled to a temperature between - 5 and -10°C. The temperature was kept below -5°C during the addition. When the addition was complete, the mixture was allowed to gradually warm to room temperature while stirring, and then allowed to stand for approx. 16 hours.

The mixture was poured onto ice which melted to give a brown aqueous solution which was acidified to pH 6 with glacial acetic acid,

and the aqueous phase was evaporated. The organic component in the residue was extracted with warm acetone and isopropanol, whereby an insoluble, inorganic residue remained which was filtered off and washed with further warm acetone and isopropanol. - The filtrate and the washing liquids were evaporated to dryness, the residue was dissolved in water and the solution neutralized to pH 7 with sodium bicarbonate. The aqueous solution was extracted with ethyl acetate and the combined organic extracts were washed with water, dried with magnesium sulfate and evaporated. under reduced pressure to give ethyl 3-(4-dimethylaminomethylphenyl)-2-formylpropionate (15.27 g) as a pale tan solid, m.p. 9 5-, 5-97°C. (iv) Nitroguanidine (7.92 g containing 25% w/w water) was washed with methanol (10 mL) into sodium methoxide (from 1.97 g sodium) in methanol (85 mL). The mixture was stirred under reflux for 45 min and ethyl 3-(4-dimethylaminomethylbenzyl)-2-formylpropionate (15.03 g) was added portionwise over 1.25 h and washed with methanol (15 mL). The mixture was stirred under reflux for an additional 22 hours.

The methanol was evaporated under reduced pressure and the residue was dissolved in water (100 ml) and extracted with chloroform. The combined chloroform extracts were washed with water. The aqueous layer and the water washings were acidified to pH 5 with glacial acetic acid. The water was evaporated under reduced pressure and isopropanol (80 mL) was added. The solid which gradually precipitated was filtered off and washed with water and isopropanol and dried in vacuo to give 2-nitroamino-5-(4-dimethylaririnomethylbenzyl)-4-pyrimidone (9.90 g) as a white solid fabric, m.p. 214-7°C.

(v) A mixture of 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (1.37 g) and 2-nitroamino-5-(4-dimethylaminomethylbenzyl)-4-pyrimidone (2.27 g) in ethanol ( 12 ml) was heated under reflux for 24 hours. The ethanol was evaporated under reduced pressure to give 2-[2-(5-methyl-4-imidazolylmethylthio)-ethylamino]-5-(4-dimethylaminomethylbenzyl)-4-pyrimidone which was washed by mixing with water, the mixture was heated and allowed to cool during approx. 16 hours and decanting the water. The residue was reacted with ethanolic hydrochloric acid (7 ml) and the ethanol was removed under reduced pressure. The residue was

recrystallized from methanol/ethanol to give the trihydrochloride (2.14 g) as a white solid, m.p. 213.5-216°C.

Example 5

A mixture of 2-(5-dimethylaminomethyl-2-furanylmethylthio)-ethylamine (1.71 g) and 2-nitroamino-5-(4-dimethylaminomethyl-benzyl)-4-pyrimidone (1.97 g) in ethanol (12 ml) was heated under reflux for 42 h. The ethanol was evaporated under reduced pressure to give 2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(4-dimethylaminomethylbenzyl)-4-pyrimidone as a brown oily residue which was washed with hot water, cooled and mixed with dilute ethanolic hydrochloric acid. Excess ethanol was evaporated under reduced pressure and the residue recrystallized from isopropanol/methanol and from ethanol to give the trihydrochloride (1.85 g) as an off-white solid, m.p. 180-184°C.-

Example 6

(i) A mixture of acetic acid (200 ml), ethyl 3-(2-furanyl)-propionate (32.2 g), dimethylammonium chloride (17.92 g) and 30% w/v aqueous formaldehyde (17.04 g ) was made and heated gently until a solution was formed. The mixture was allowed to cool and stand for approx. 36 hours at room temperature. •Acetic acid was removed by evaporation under reduced pressure to give an oil which was dissolved in water adjusted to basic pH 10-11. The aqueous solution was extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over magnesium sulfate and the ethyl acetate was evaporated under reduced pressure to give a brown oil which was distilled to give ethyl 3-(5-dimethylaminomethyl)-2-furanyl)propionate as a colorless oil (19, 25 g), c.p. 0.7 mm 108-112°C.

(ii) Ethyl 3-(5-dimethylaminomethyl-2-furanyl)-propionate (19 g) and ethyl formate (9.33 g) were added dropwise with stirring to a suspension of sodium hydride (50% in oil, 4.0 g ) in 1,2-dimethoxyethane (50 mL) which had been pre-cooled to -40°C. The temperature was kept below -30°C during the addition, and when this was complete the mixture was allowed to gradually warm up to room temperature during approx. 16 hours. A solid, brown mass was formed which was put on ice. When the ice melted, a solution was formed which was extracted with ethyl acetate. The aqueous phase was acidified with acetic acid to pH 4.5, evaporated to dryness under reduced pressure and azeotroped with n-propanol to give a brown oil. The oil was extracted with hot acetone to remove acetone-insoluble inorganic material which was filtered from the acetone solution and washed with hot acetone. The acetone solution was evaporated to dryness to give ethyl 3-(5-dimethylaminomethyl-2-furanyl)-2-formyl-propionate (21.22 g)

which was used in the next step without purification.

(iii) Nitroguanidine (10.85 g containing 25% w/w water)

was added to a solution of sodium (5.75 g) in methanol (100 ml) and the mixture was stirred under reflux for 0.5 h. The mixture was allowed to cool and a solution of ethyl 3-(5-dimethylaminomethyl-2-furanyl)-2-formylpropionate (21.22 g) in methanol (80 ml) was added dropwise to the cooled mixture. The mixture thus obtained was then stirred under reflux heating for 18 hours after which the solvent was evaporated under reduced pressure and the residue mixed with hot acetone to give a solution and a solid residue which was removed by filtration, washed with more hot acetone, and acetone - the washing liquids were mixed with the solution. The combined solution was evaporated under reduced pressure to give an oil which was crystallized from isopropanol to give 2-nitroamino-5-(5-dimethylaminomethyl-2-furanylmethyl-4-pyrimidone) (5.42 g),

sm.p. 210°C (splitting) .

(iv) A solution of 2-(5-methyl-4-imidazolylmethylthio)-

Ethylamine (1.28 g) and 2-nitroamino-5-(5-dimethylaminomethyl-2-furanylmethyl)-4-pyrimidone (2.2 g) in pyridine (20 ml) were heated under reflux for approx. 16 hours. The pyridine was evaporated under reduced pressure, azeotroped with >water to remove pyridine and water was removed by azeotroping with n-propanol. The oily residue was chromatographed over a silica gel column eluting with methanol in ethyl acetate. Evaporation of the eluent gave a glassy solid residue

which was dissolved in methanol. Ether was added to precipitate 2-(5-methyl-4-imidazolylmethylthio)-ethylamino]-5-(5-dimethyl-aminomethyl-2-furanylmethyl)-4-pyrimidone (1.19 g) as a white,

solid, m.p. 108-110°C.

Example 7

A solution of 2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamine (1.29 g) and 2-nitroamino-5-(5-dimethylaminomethyl-2-furanylmethyl)-4-pyrimidone in pyridine (15 ml ) was heated under reflux cooling for approx. 20 hours. The pyridine was evaporated under reduced pressure. The last traces of pyridine were removed by azeotroping with water and water was removed by azeotroping with n-propanol. The oily residue was chromatographed over a silica gel column eluting with methanol in ethyl acetate (10% v/v). Evaporation of the eluent gave 2-[2-(5-dimethylamino-methyl-2-furanyl-methylthio)ethylamino]-5-(5-dimethylaminomethyl-2-furanylmethyl)-4-pyrimidone as an oil which was transferred to the trihydrochloride using of an excess of ethanolic HCI. The salt was recrystallized from isopropanol to give a white solid (0.72 g), m.p. 181-183°C.

Example 8

2-(2-guanidino-4-thiazolylmethylthio)ethylamine dihydrochloride (2.00 g) was added to a solution of sodium (0.3 g) in ethanol (15 ml). After the solution was refluxed for 0.5 hour, the ethanol was evaporated under reduced pressure and dry pyridine (40 ml) was added. 2-Nitroamino-5-(5-dimethylamino-methyl-2-furanyl)-4-pyrimidone (1.90 g) was added and the mixture was refluxed for 20 hours. The pyridine was evaporated under reduced pressure, and the oily residue azeotroped with water. The residue was further washed with water, and the water decanted. The remaining oil was then azeotroped with n-propanol and treated with decolorizing charcoal. The decolorized residue was dissolved in ethanolic HCl and evaporated to dryness under reduced pressure. The resulting hydrochloride salt, which was highly hygroscopic, was converted to the free base by dissolving it in water, and the aqueous solution was basified with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate phase was dried and evaporated to dryness to give a yellow solid which was recrystallized from ethyl acetate to give 2-[2-(guanidino-4-thiazolylmethylthio)-

ethylamino]-5-(5-dimethylaminomethyl-2-furanylmethyl)-4-pyrimidone (0.34 g), m.p. 113-116°C.

Example 9

A solution of 2-(5-dimethylaminomethyl-2-thienyl-methylthio)ethylamine (1.47 g) and 2-nitroamino-5-(5-dimethylamino-methyl-2-thienylmethyl)-4-pyrimidone (2.0 g ) in pyridine (10 mL)

was refluxed overnight. The pyridine was removed under reduced pressure and the last traces of pyridine were removed by azeotroping with water to give 2-(5-dimethylaminomethyl-2-thienylmethylthio)-ethylamino-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone like an oil. The resulting oil was washed by decantation with water.

The brown oil thus formed was dissolved in diethyl ether and ethanolic hydrochloric acid solution was added. The liquid was evaporated and the remaining solid was recrystallized from methanol/ethanol to give the hydrochloride (1.9 g), m.p. 212-215°C.

Example 10

(i) A mixture of ethyl 3-(6-methyl-3-pyridyl)-propionate (38.65 g), hydrogen peroxide (30%, 25 ml) and glacial acetic acid (100 ml)

was stirred at 95-100°C for 5.5 hours. The acetic acid was evaporated under reduced pressure, and the residue was diluted with water (to about 100 ml). The aqueous mixture was adjusted to pH 9 with aqueous sodium carbonate solution and extracted with ethyl acetate. The extracts were washed with water, dried (MgSO 4 ), and ethyl acetate was evaporated under reduced pressure to give ethyl 3-(6-methyl-3-pyridyl)-propionate-N-oxide as a brown oil (31.51 g ). Concentration of the aqueous layer further (ca. 100 mL) and continuous extraction for 6 h with ethyl acetate gave a further amount (3.38 g) of the product, also as a brown oil.

(ii) Trifluoroacetic anhydride (100.59 g) was added dropwise over 45 minutes with stirring to a pre-cooled (2°C) solution of ethyl 3-(6-methyl-3-pyridyl)-propionate-N-oxide ( 59.40 g, 0.284 mol) in dry dichloromethane (500 mL) while maintaining the temperature between 5 and 8°C. The mixture was then allowed to stand for 20 hours at room temperature with light excluded. Methanol (40 mL) was added to the solution and the dichloromethane was removed by distillation. The residue was dissolved in water and adjusted to pH 6 with aqueous sodium bicarbonate solution. The solution was extracted with chloroform, the chloroform extracts were washed with water, dried (MgSO 4 ) and the chloroform was removed by distillation to give a brown oil which was dissolved in methanol (120 ml) and treated with ethanolic hydrochloric acid (50 ml). Evaporation of the solvent gave the ethyl 4-(6-hydroxymethyl-3-pyridyl)-propionate hydrochloride as a brown oil (66.57 g).

(iii) Tlonyl chloride (35.5 ml) was added dropwise under re-

stirring during 15 minutes to a pre-cooled solution (0°C) of ethyl 3-(6-hydroxymethyl-3-pyridyl)-propionate hydrochloride (66.57 g) in chloroform (300 ml) while the temperature was kept at 0-2°C. When the addition was complete, the reaction mixture was stirred for an additional 2.5 hours, allowed to warm to room temperature and then heated to 40°C for approx. 15 minutes. Chloroform and excess thionyl chloride were evaporated under reduced pressure. The remaining thionyl chloride was removed by addition of benzene and evaporation under reduced pressure to give a brown oil.

The brown oil was dissolved in ethanol (300 ml), the solution was cooled (0°C) and a solution of dimethylamine

(33% w/v) in ethanol was added dropwise with stirring

within 20 minutes. When the addition was complete, stirring was continued for 1 hour while the reaction mixture was allowed to warm to room temperature. The reaction mixture was then allowed to stand overnight.

The ethanol was evaporated under reduced pressure, and the residue

was dissolved in water and adjusted to pH 9 with aqueous sodium bicarbonate solution. The aqueous solution was extracted with ethyl acetate, washed with water, dried (MgSO 4 ) and evaporated. under reduced pressure to give ethyl 4-(6-dimethylaminomethyl-3-pyridyl)propionate (55.01 g) as a brown oil. The oil was dissolved in methanol and reacted with an excess of ethanolic hydrochloric acid. Evaporation of the solvent under reduced pressure gave a

oil which was recrystallized from isopropanol/ethyl acetate to give 3-(6-dimethylaminomethyl-3-pyridyl)-propionate dihydrochloride (46.85 g) as a pale tan solid, m.p. 124-8°C. Evaporation of the mother liquor gave a residue which was recrystallized from isopropanol/ethyl acetate to give a further

(1.55 g) of the product.

(iv) A mixture of vacuum-dried ethyl 3-(6-dimethylaminomethyl-3-pyridyl)-propionate (28.02 g) by neutralization of the dihydrochloride salt with sodium bicarbonate, and ethyl formate (13.18 g) was added dropwise. with stirring to a cooled (-2°C) suspension of sodium hydride (50% in oil, 7.12 g) in 1,2-dimethoxyethane (50 mL) over 30 minutes while maintaining the temperature of the reaction mixture at 0°C . Stirring was continued while the reaction mixture was allowed to warm to room temperature, and the mixture was then allowed to stand overnight.

The reaction mixture was poured onto ice and a brown solution was formed which was extracted with petroleum ether (b.p. 40-60°C) and diethyl ether. The extracts were collected and washed with water. The water washes were mixed with the aqueous solution,

and water were evaporated and the last traces removed by azeotroping with n-propanol to give 2-formyl-3-(6-dimethylamino-methyl-3-pyridyl)-propionate (22.81 g) as a brown oil.

(v) Nitroguanidine (11.96 g containing 25% w/w water)

was washed with methanol (15 mL) into a solution of sodium methoxide in methanol (from 2.97 g sodium and 55 mL methanol). The mixture was stirred for 45 minutes under reflux

and then a solution of ethyl 2-formyl-3-(6-dimethyl-aminomethyl-3-pyridyl)propionate (22.78 g) in methanol (50 ml) was added dropwise over 1.25 hours and the mixture was then refluxed for 19 hours.

The methanol was evaporated under reduced pressure and the residue dissolved in water (100 ml). The aqueous solution was extracted with chloroform and the chloroform extracts were washed with water.

The aqueous phase and the water washings were collected and adjusted to pH 5 with acetic acid. The solvent was evaporated under reduced pressure and it was dried by azeotroping with isopropanol. The residue was extracted twice with boiling acetone/n-propanol and recrystallized from water to give 2-nitroamino-5-(6-dimethylaminomethyl-3-pyridylmethyl)-4-pyrimidone (9.31 g) as a pale green solid , sm.p. 234-8°C.

(vi) A mixture of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.37 g), 2-nitroamino-5-(6-dimethylaminomethyl-3-pyridylmethyl)-4-pyrimidone (2.28 g) in pyridine was heated under reflux for 22 hours. Pyridine (12 mL) was evaporated under reduced pressure to give [2-(5-methyl-4-imidazolyl-methylthio)ethylamino]-5-(6-dimethylaminomethyl-3-pyridylmethyl)-4-pyrimidone as a brown oily residue which was washed with water by decantation. The residue was dissolved in dilute ethanolic hydrochloric acid and excess solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/dilute ethanolic hydrochloric acid and then twice from methanol/ethanol to give the tetrahydrochloride (0.82 g) as a light tan solid, m.p. 167-170°C.

Example 11

A mixture of 2-(5-dimethylaminomethyl-2-furanylmethylthio)-ethylamine' (1.71 g) and 2-nitroamino-5-(6-dimethylaminomethyl-~3-pyridylmethyl)-4-pyrimidone (1.98 g) in pyridine (12 ml) was heated under reflux for 22 h, allowed to cool and the pyridine evaporated under reduced pressure. The residue was washed by decantation with hot water, dissolved in dilute ethanolic hydrochloric acid and the solvent evaporated to give 2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(6-dimethylaminomethyl-3-pyridylmethyl)- 4-pyrimidone. The residue was recrystallized from methanol/dilute ethanolic hydrochloric acid and from methanol/ethanol to give 3.8 hydrochloride 1.4 hydrate (0.85 g) as a pale tan solid, m.p. 142-5WC. Evaporation of the mother liquors and recrystallization of the residue from methanol/ethanol gave further product (0.62 g), m.p. 138-142°C.

Example 12

(i) Raney nickel (about 7 g) was added to a solution of 3-dimethylaminomethylbenzonitrile (78.30 g) and sodium hypophosphite monohydrate (170.0 g) in water:acetic acid:pyridine 1:1:2 (1600 ml) The mixture was stirred for 3 hours at 43-45°C and then allowed to cool.

Raney nickel was removed by filtration through diatomaceous earth, and the filter cake was washed with ethanol. The combined washing liquids and filtrate were evaporated under reduced pressure to a smaller volume (approx. 600 ml) and diluted with water (250 ml). The volume of the solution was again reduced (to about 600 ml), adjusted to pH 8 with aqueous potassium carbonate solution and extracted with ethyl acetate. The extract was washed with water, dried (MgSO 4 ) and the solvent evaporated to give 3-dimethylaminomethylbenzaldehyde (62.88 g) as a straw colored liquid. (ii) A mixture of 3-dimethylaminomethylbenzaldehyde (32.64 g), monomethyl malonate (29.07 g), pyridine (100 ml) and piperidine (2 ml). was heated under reflux for 5 hours with stirring. The reaction mixture was allowed to cool, and the pyridine was removed under reduced pressure. The residue was dissolved in diethyl ether and the ether solution was washed with water, dried (MgSO 4 ) and evaporated under reduced pressure and dried in vacuo to give ethyl 3-(dimethylaminomethyl)cinnamate (40.39 g) as a straw colored oil . (iii) A mixture of ethyl 3-(dimethylaminomethyl)cinnamate (40.39 g), and palladium-on-charcoal (10%, ca. 0.3 g) in ethanol (170 mL) was hydrogenated at an original pressure of 344 kPa until the theoretical amount of hydrogen uptake was registered. The catalyst was removed by filtration through diatomaceous earth, washed with ethanol, and the combined filtrate and washings were evaporated under reduced pressure to give ethyl 3-(3-dimethylaminomethylphenyl)propionate (38.63 g) as a pale straw colored liquid . (iv) A mixture of ethyl 3-(3-dirnethylaminomethylphenyl)propionate (38.63 g) and ethyl formate (18.25 g) was added dropwise with stirring to a pre-cooled (-5°C) suspension of sodium hydride (50 % in oil, 9.85 g) in 1,2-dimethoxyethane (60 mL)

during 1.75 hours, the temperature of the reaction mixture being kept below 0°C during the addition. The mixture was allowed to warm to room temperature with continuous stirring, and then allowed to stand overnight.

The mixture was poured onto ice and a brown aqueous solution formed which was extracted with petroleum ether (b.p. 40-60°C) and diethyl ether and the aqueous phase was collected. The extracts were washed with water, and the combined washings and the aqueous phase were acidified to pH 6. The aqueous phase was evaporated under reduced pressure to give a brown oil which was dried by azeotroping with isopropanol. The dried residue was extracted with hot isopropanol/acetone, leaving an inorganic solid which was removed by filtration through diatomaceous earth and washed with more isopropanol/

acetone. The filtrate and washings were collected and suspended

in water which was adjusted to pH 8 with aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate. The extract was washed with water, dried (MgSO 4 ) and evaporated under reduced pressure to give ethyl 2-formyl-3-(3-dimethylaminomethylphenyl)-propionate (20.04 g) as a light brown oil.

(v) Nitroguanidine (10.56 g containing 25% w/w water) was washed with methanol (10 mL) into a solution of sodium methoxide in methanol (from 2.62 g sodium and 50 mL methanol). The mixture was stirred under reflux for 0.75 hour

and a solution of 2-formyl-3-(3-dimethylaminomethylphenyl)-propionate (20.04 g) in methanol (50 ml) was then added dropwise with stirring over 1 hour. The mixture was stirred while heating under reflux for 22 hours.

The methanol was evaporated under reduced pressure and the residue was dissolved in water (100 mL), extracted with chloroform, and the chloroform extracts were washed with water. The aqueous phase was acidified to pH 5 with glacial acetic acid. An oil precipitated which on standing was cooled and solidified to give 2-nitroamino-5-(3-dimethylaminomethylbenzyl)-4-pyrimidone (8.79 g) as a pale cream solid, m.p. 232-5°C.

Evaporation of the mother liquor gave an oily residue which

when washed with water and boiled with isopropanol, solidified to give a further quantity (1.57 g) of the pale, cream-colored solid product, m.p. 225-6°C.

(vi) A mixture of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.37 g) and 2-nitroamino-5-(3-dimethylaminomethylbenzyl)-4-pyrimidone (2.27 g) in pyridine (12 ml) was refluxed for 18 hours. The solvent was evaporated under reduced pressure and the residue was washed with water by decantation, dried and reacted with maleic acid in acetone. The solvent was evaporated and the residue, 2-[5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-dimethylaminomethylbenzyl)-4-pyrimidone, was recrystallized

from isopropanol-methanol to give the trimamate (3.07 g) as a pale tan solid, m.p. 140.5-142.5°C.

Example 13

A mixture of 2-(5-dimethylaminomethyl-2-furanylmethylthio)-ethylamine (1.71 g) and 2-nitroamino-5-(3-dimethylaminomethylbenzyl)-4-pyrimidine (1.97 g) in pyridine (12 mL) was refluxed for 23 hours. Excess pyridine was then evaporated to give 2-(2-(5-dimethylaminomethyl-2-furanylmethylthio)-ethylamino]-5-(3-dimethylaminobenzyl)-pyrimidone as an oily residue which was washed with water by decantation.

The residue was then dissolved in dilute ethanolic hydrochloric acid, and excess solvent was removed. The residue was recrystallized from isopropanol/ethanol and then from ethanol to give the trihydrochloride (2.51 g) as a light tan solid, m.p. 182.5 to 185°C.

Example 14

(i) A mixture of diethyl sulfate (57.41 g) and tri-n-propylamine was added dropwise with stirring to a solution of furanyl acrylic acid (34.53 g) in acetone (150 ml). When the addition was complete, the mixture was refluxed for 6 hours. .Acetone was evaporated under reduced pressure. The resulting oily residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, dried (MgSO 4 ), and the solvent was evaporated to give ethyl 3-(2-furanyl)acrylate (46.7 g) as a brown oil. . (ii) A mixture of ethyl 3-(2-furanyl)acrylate (46.7 g) and conc. ammonium hydroxide solution (25 ml) was hydrogenated in the presence of Raney nickel (500 mg) at 35°C until the theoretical amount of hydrogen was taken up. Raney nickel was removed by filtration through diatomaceous earth and the filtrate was evaporated under reduced pressure to give a brown oil. The oil was dissolved in ethyl acetate, washed with distilled water, dried (MgSO 4 ) and the solvent was evaporated under reduced pressure to give ethyl 3-(2-furanyl)-propionate (33.77 g) as a brown oil.

(lii) A mixture of ethyl 3-(2-furanyl)-propionate (33.77 g)

and ethyl formate (22.22 g) was added dropwise with stirring to a precooled (0°C) suspension of sodium hydride (50% in oil, 8.45 g) in dimethoxyethane (70 mL), keeping the temperature below 0°C during the addition. The reaction mixture

allowed to warm to room temperature and then poured onto ice

and water and extracted with ethyl acetate. The aqueous layer was acidified to pH 4 and extracted again with ethyl acetate. These other ethyl acetate extracts were combined, dried (MgSO 4 ) and evaporated under reduced pressure to give ethyl 3-(2-furanyl)-2-formylpropionate (19.0 g).

(iv) Nitroguanidine (12.59 g containing 25% w/w water)

was added to a solution of sodium urn methoxide in methanol (from 6.25 g of sodium and 100 ml of methanol), and the mixture was refluxed until dissolution was complete. The mixture was cooled and ethyl 1-3-(2-furanyl)-2-formylpropionate (19 g) was added. This mixture was then refluxed for approx. 16 hours. The methanol was evaporated under reduced pressure to give an oil which was mixed with water and acidified to pH 4

with glacial acetic acid. Cooling and trituration of the aqueous mixture gave a solid which was recrystallized from glacial acetic acid to

give 2-nitroamino-5-(2-furanylmethyl)-4-pyrimidone (6.48 g),

sm.p. 18 3-4°C.

Evaporation of the mother liquors gave a further quantity

(2.49 g) product, m.p. 181-2°C.

(v) A solution of 2-nitroamino-5-(2-furanylmethyl)-4-pyrimidone (5.24 g) in ethanol (50 ml) was added to a solution of 2-[2-(2-furanyl)methylthio ]ethylamine (3.49 g). The mixture was refluxed for 24 hours. The reaction was stopped, and the ethanol was evaporated to give an oil which was dissolved in ethyl acetate containing traces of methanol, and the resulting solution was extracted with distilled water. The aqueous phase was back-extracted with ethyl acetate. The ethyl acetate extracts were pooled and extracted with distilled water,

dried (MgSO4) and evaporated to dryness to give an oil

(4.74 g). The oil was chromatographed over a silica gel column using first petroleum ether 40-60°C, ethyl acetate

(80%, 20%) and then petroleum ether 40-60°C, ethyl acetate (60%, 40%) The eluate containing the desired product was evaporated to dryness to give an oil (3.36 g) which was dissolved in ethyl acetate and chromatographed over a silica gel column eluting with ethyl acetate. The eluate containing the product was evaporated to dryness to give 2-[2-(2-furanyl)-methylthio]-ethylamino]-5-(2-furanyl)-4-pyrimidone as an oil (2.28 g) which was

dried over ^2^5^ vacuum.

(vi) Bis-dimethylaminomethane (1.23 g) was added with stirring to 2-[2-(2-furanylmethylthio)ethylamino]-5-(2-furanylmethyl)-4-pyrimidone (0.8 g) suspended in glacial acetic acid (8 ml). The mixture was then stirred at room temperature for 3 hours and allowed to stand

for about. 16 hours. The acid was evaporated under reduced pressure azeotropically with water. The remaining oil was dissolved in water, filtered and the filtrate was adjusted to pH .9 using aqueous sodium carbonate solution. The basic solution was extracted with ethyl acetate, and the extracts were dried. (MgSO^) and evaporated to give 2-[2-,(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(5-dimethylaminomethyl-2-furanyl-methyl)-4-pyrimidone as an oily residue (1 .01 g). The oily residue was dissolved in the smallest possible volume of ethanol and then acidified with ethanolic hydrochloric acid. The acidic solution was then evaporated to dryness and the remaining oil crystallized from isopropanol/ethanol to give the white solid trihydrochloride salt (1.33 g), m.p. 177-9°C.

Example 15

(i) 2-hydroxymethyl-4-cyanopyridine (6.71 g) was added portionwise

■over 15 minutes to thionyl chloride (24.6 g) with stirring. Stirring was continued for minutes. Excess thionyl chloride was evaporated under reduced pressure to give a solid residue to which diethyl ether (15 mL) was added. This mixture was cooled (to about 0°C), and a solution of dry dimethylamine (15 mL) in dry diethyl ether (15 mL) was added dropwise over 10 minutes to the mixture. This new mixture was stirred for 30 minutes and allowed to stand (for about 16 hours).

The mixture was washed with water, and the water-washing liquids

was extracted with ether and ethyl acetate. The organic phases were combined, dried (MgSO 4 ) and the solvent evaporated to give 4-cyano-2-dimethylaminomethyl-pyridine (8.02 g) as a straw colored oil.

(ii) 4-cyano-2-dimethylaminomethyl-pyridine is transferred to 2-nitroamino-5-(2-dimethylaminomethyl-4-pyridylmethyl)-4-pyrimidone by the method described in example 12 (i) to (v). (iii) Reaction of 2-nitroamino-5-(2-dimethylamino-methyl-4-pyrimidone with 2-(5-methyl-4-imidazolylmethylthio)ethylamine by the method indicated in example 12 (vi) gives 2-[2-( 5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(2-dimethylaminomethyl-4-pyridylmethyl)-4-pyrimidone.

Claims (10)

1. Process for the preparation of a therapeutically active compound of formula (I): where W is a 2-furanyl or 2-thienyl group which is optionally substituted in the 5-position with a group R' 1 R 2 NCCI-^); a phenyl group substituted in the 3- or 4-position by a 12 group R R (CH 2 )^-; a 4-imidazoyl group which is optionally substituted in the 5-position with methyl or bromine; a 2-pyridyl group which is optionally substituted in the 3-position with C 1 -C alkyl, C^_^ alkoxy, halogen, amino or hydroxy; a 2-thiazolyl group or a 2-guanidino-4-thiazolyl group; X is methylene or, sulfur, and Y is methylene or, provided X is methylene and W is a substituted phenyl group, oxygen; Z is hydrogen or C 1-4 alkyl; and B is a 2-furanyl or 2-thienyl group which is substituted in the 5-position by a group 12 R R N(CH„) -; a phenyl group substituted in the 3- or 4-position \ 2 with a group R R NfCl-^) - or a 3-pyridy.L-g.ruppe substituted in the 5- or 6-position or a 4-pyridyl group substituted in the 2-position or a 2-pyridyl group substituted in the 4- or 5- 12 position with a group R"'R NfCI-^) ; 12R^" and R^ are C 1-4 alkyl or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or morpholino group; m is 1 to 4; and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of formula (II): where W and Y are as defined under formula (I) and D is -XCI-^Cf-^NI-^ or, provided that Y is methylene, a thiol-displaceable group, reacted with a pyrimidone- ■ derivative with formula (III): where B"^ is 2-furanyl, 2-thienyl or B, where B and Z are as defined under formula (I) and A is a group which can be replaced by an amine when D is -XCH2 CH2 NH2 , or A is HS -CH2 CH2 NH when D is a thiol-displaceable group, and then, when B^ is 2-furanyl or 2-thienyl, and optionally when W is 2-furanyl or 2-thienyl, the product thus obtained is reacted with a Mannich reagent which provides the substituent R <1> R <2> N(CH„ ) - where m is 1, and then the obtained compound of formula (I) is converted into a salt. 2. Process as stated in claim 1, characterized in that a starting material of formula (III) is used where B" <*> " is or is converted to 5-dimethylaminomethyl-2-furanyl, 6-dimethylaminomethyl-3-pyridyl or 2- dimethylaminomethyl-4-pyridyl. 3. Method as stated in claim 1, characterized in that a starting material of formula (II) is used where W is or is converted to 2-furanyl or 2-thienyl which is optionally substituted in the 5-position J with R 1 R 2N(CH 2 „) m- ; 4-imidazolyl which is optionally substituted in the 5-position with methyl or bromine; 2-pyridyl which is optionally substituted in the 3-position with C, _ . alkyl, C₁₋₄ alkoxy, halogen, amino or other. hydroxy; 2-thiazolyl or 2-guanidino-4-thiazolyl. 4. Method as set forth in one of claims 1 to 3, characterized in that a starting material of formula (II) is used where W contains the group 12 R R N(CH2)^- or where said group is introduced, D is hydroxy, C^ _^ alkoxy or acetoxy, and the reaction is carried out under acidic conditions. 5. Method as stated in one of claims 1 to 3, characterized in that a starting material of formula (II) is used where W is 2-furanyl or 2-thienyl, D is sulfonyloxy, chlorine, bromine or triarylphosphonium, and the reaction is carried out in the presence of a base. 6. Method as stated in claim 5, characterized in that a starting material of formula (II) is used where D is hydroxy or chlorine. 7. Process as set forth in claim 1, characterized in that a starting material of formula (III) is used where A is nitroamino, C 1 alkylthio, chlorine or bromine. 8. Method as set forth in claim 1, characterized in that the Mannich reagent is prepared in situ from an amine R R NH where R pg R is as 12 defined under formula (I), and formaldehyde, and R and R are both C 1 - 2 alkyl. 9. Method as stated in claim 1, characterized in that a pre-formed Mannich reagent is used. 10. Method as set forth in claim 9, characterized in that dimethylethylene ammonium chloride or iodide or a bis-(di-C 1 -alkylamino)methane is used as Mannich reagent.